PROJECT SUMMARY/ABSTRACT Non-alcoholic steatohepatitis (NASH)-related cirrhosis is likely to be the leading indication for liver transplantation in the United States by 2020. Despite the growing incidence, a lack of clarity in the mechanisms of NASH pathogenesis has hindered our ability to develop effective diagnostic and therapeutic strategies. There is substantial scientific evidence suggesting a strong relationship between diet-induced gut dysbiosis, intestinal epithelial barrier dysfunction and CD4 T cell-induced hepatic inflammation in NASH development. My preliminary data reveal a role for diet-induced increases in pro-inflammatory CD4 T cells in hepatic and intestinal mucosal inflammation in a mouse model of NASH. These novel data along with the published literature provide a strong premise to further investigate the mechanistic link between CD4 T cell-mediated hepatic inflammation and intestinal epithelial barrier disruption in NASH. In Aim 1, I will determine how the gut microbiota facilitate CD4 T cell-mediated intestinal epithelial barrier disruption. In Aim 2, I will investigate mechanisms of diet-induced CD4 T cell activation and trafficking to the gut mucosa, and the role CD4 T cells play in regulating intestinal epithelial barrier integrity. In Aim 3, I will focus on the mechanisms of CD4 T cell- mediated hepatic inflammation in NASH development. Given the importance of CD4 T cells in the regulation of hepatic and intestinal immunity in NASH, the relevance of gut dysbiosis to NASH, and the therapeutic potential of targeting gut microbiota and immune cells, this proposal represents a new perspective in NASH that is highly innovative and clinically relevant. A K01 award will allow me to work alongside the world's leading experts in liver disease and immunology as I pursue my goal to become an independent biomedical investigator. The extraordinary mentorship relationships that will develop will improve my skills as an investigator as well as answer significant important questions related to metabolic diseases of the liver. Further, this award will immeasurably advance my training in liver disease under the guidance of Dr. Frank Anania. As a physician-scientist who has made significant contributions in the field of metabolic liver disease, Dr. Anania and his lab provide an ideal environment to study NASH. My mentorship committee includes world-renowned T cell immunologist, Dr. Rafi Ahmed, who will provide me with important scientific counsel and critical access to cutting-edge immunological tools and techniques to comprehensively investigate the role of T cells in NASH. Also on my committee is Dr. Arash Grakoui, the nation's leading expert on hepatic T cells and their role in chronic viral infection. Moreover, the exceptional educational environment at Emory University School of Medicine will augment my training by providing institutional programs, facilities, and opportunities for collaboration. A K01 award will provide significant support at this pivotal stage of my career, allowing me to make a substantial commitment to study the role of immune regulation in metabolic diseases of the liver.